Melt-blended formulations containing active agents and solubilizers exist in the art.
U.S. Pat. No. 4,944,949 discloses micelles of non-steroidal anti-inflammatory drugs (NSAIDS) with nonionic surfactants such as poloxamers (col. 5, line 31). Micelles are aggregates in which surfactant molecules are arranged in a spheroidal structure, with the hydrophobic regions at the core and the hydrophilic regions at the other surfaces. Drug:surfactant ratios of 1:5.7 to 1:50 are disclosed at column 12, line 57.
U.S. Pat. No. 5,281,420 shows tebufelone, an anti-inflammatory agent, in solid dispersions containing 15% to 75% tebufelone and 25% to 65% of a poloxamer surfactant (col. 1, lines 35-51).
U.S. Pat. No. 5,525,355 deals with laxative compositions which contain poloxamer surfactants, as stool softeners, melt-blended with stimulants. The ratio of surfactant to stimulant is 2:1 to 20:1 (col. 2, line 22+). The compositions are administered in hard gelatin capsules.
EPO Application 0 317 780, published May 31, 1989, shows quick-release and sustained-release formulations containing dihydropyridine calcium channel blockers and poloxamer surfactants. The quick release compositions contain 0.15:1 to 0.5:1 of hydroxypropylmethylcellulose to dihydropyridine/poloxamer complex (p. 6, l. 48-49). The complex contains 1:1 to 1:10 ratios of drug to surfactant (page 6, lines 25-27).
WO97/02017, published Jan. 23, 1997, discusses oral dosage forms which contain a solid dispersion of an active ingredient in a poloxamer polymer. The ratio of active agent to poloxamer is 0.1:1.0 to 10.0:1.0 (page 3, line 280.
U.S. Pat. No. 4,727,109 shows liquid preparations containing an active agent and a carrier system consisting of a hydrophilic component, a hydrophobic component and a solubilizer. The hydrophilic component may be a polyethylene glycol or a polyoxyethylene/polyoxypropylene copolymerizate. See column 2, lines 35-44.
U.S. Pat. No. 5,456,923 describes solid dispersions of drugs in polymers made by extruding the two together and pulverizing the extrudate. Polyoxyethylene/polyoxypropylene copolymers are disclosed, at column 3, lines 33-4, as plasticizers.
U.S. Pat No. 5,292,461 deals with pellets produced by spraying an active agent with a wetting agent. Polyethylene glycols are disclosed as lubricants (col. 7, l. 62) and agents which influence the release of the active ingredient (col. 8, l. 1-2). Poloxamers are recited as surface-active agents (col. 7, l. 65).
The art has not successfully blended polymeric solubilizing agents with actives to directly produce stable solid microspheres of uniform size. This invention describes such microspheres.